These studies will investigate the transneuronal influence of olfactory receptor cells on neuronal survival and neurotransmitter expression in the olfactory bulb and other brain regions including the basal forebrain. Odor discrimination in disease and during normal aging diminishes largely due to effects through olfactory receptor cells. These cells are unique because in response to either lesion or during normal cyclic receptor cell degeneration, they are replaced from immature stem cells, which replicate, differentiate and send out axons to reinnervate the olfactory bulb. Lesions of these cells have been shown to alter neurotransmitter synthesis in dopamine systems intrinsic to the olfactory bulb. To study the receptor afferent interactions with brain the following specific problems will be addressed: 1) The transneuronal effects of receptor cell lesions on other neurotransmitter systems will be established. At a molecular level, a cDNA probe to tyrosine hydroxylase will be utilized to determine if the lesion induced decrease in the activity of the neurotransmitter synthetic enzyme, tyrosine hydroxylase (TH), can be attributed to a decrease in the level of TH specific messenger RNA. 2) The ability of olfactory receptor cells to transneuronally transport intranasally applied substances, including toxins, will be established using lectins and toxins. Long term cytotoxic effects of ligands will be tested in regions known to have direct or indirect contact with receptor cell afferents including olfactory bulb and forebrain. 3) Intra- and inter-specific differences in the above phenomena wil be determined especially with respect to anomalies in receptor cell afferent input and developmental influences. 4) The relationship of receptor afferent neuronal activity to the regulation of phenotypic expression in CNS and to transneuronal transport phenomena will be addressed. 5) The ontogeny of transmitters in olfactory bulb neurons will be correlated with their receipt of afferent input. These data should provide insight into the transneuronal role of olfactory receptor cell efferent input in normal and abnormal expression of neurotransmitter phenotypes in adults subjected to lesions as well as establishing their influence during development. The studies also have ramifications with respect to degenerative brain syndromes (for example, Alzheimer's disease) because of the ability of receptor cells to transneuronally transport substances contained in inspired air, some cytotoxic, from the nasal epithelium to the forebrain.